Clinical case study meets population cohort: identification of a BRCA1 pathogenic founder variant in Orcadians

Abstract

We multiply ascertained the BRCA1 pathogenic missense variant c.5207T > C; p.Val1736Ala (V1736A) in clinical investigation of breast and ovarian cancer families from Orkney in the Northern Isles of Scotland, UK. We sought to investigate the frequency and clinical relevance of this variant in those of Orcadian ancestry as an exemplar of the value of population cohorts in clinical care, especially in isolated populations. Oral history and birth, marriage and death registrations indicated genealogical linkage of the clinical cases to ancestors from the Isle of Westray, Orkney. Further clinical cases were identified through targeted testing for V1736A in women of Orcadian ancestry attending National Health Service (NHS) genetic clinics for breast and ovarian cancer family risk assessments. The variant segregates with female breast and ovarian cancer in clinically ascertained cases. Separately, exome sequence data from 2088 volunteer participants with three or more Orcadian grandparents, in the ORCADES research cohort, was interrogated to estimate the population prevalence of V1736A in Orcadians. The effects of the variant were assessed using Electronic Health Record (EHR) linkage. Twenty out of 2088 ORCADES research volunteers (~1%) carry V1736A, with a common haplotype around the variant. This allele frequency is ~480-fold higher than in UK Biobank participants. Cost-effectiveness of population screening for BRCA1 founder pathogenic variants has been demonstrated at a carrier frequency below the ~1% observed here. Thus we suggest that Orcadian women should be offered testing for the BRCA1 V1736A founder pathogenic variant, starting with those with known Westray ancestry.

Fig. 1. Grandparental ancestry of carriers in ORCADES.

The first eight columns are parishes or isles of Orkney. The remainder are locations elsewhere in Scotland, or unknown. Of all 80 grandparents of the carriers, 60% were from Westray, with the majority of the remainder coming from other parishes or isles of Orkney.

Fig. 2. Outline pedigree of two kindreds (A and B) from the ORCADES study.

Filled circles are breast or ovarian cancers, red outlines are sequenced V1736A carriers, dotted red outlines are obligate carriers. The founders of kindred A, the largest, were born in Westray in the 1760s. All four of the other kindreds also eventually lead back to Westray common ancestors, in the 19th century (but with deeper ancestry there back to the same time depth). In kindred C, mostly resident in the East Mainland of Orkney, the Westray common ancestors were born in the early 1800s.

Fig. 3. Haplotype sharing.

a Genome-wide identity-by-descent sharing between two ORCADES carriers from different kindreds. In addition to the shared BRCA1 haplotype on chromosome 17, background sharing due to Westray ancestry can be seen across the genome. b Haplotype sharing across chromosome 17 for all pairwise combinations of representatives of each of the four kindreds in ORCADES. Mb, megabase; IBD, identity-by-descent; * denotes the shortest shared haplotype.